Equilibrium solubility, solvation and dissolution thermodynamics, and DFT study of 18β-glycyrrhetinic acid in solutions of 1,4-dioxane/N,N-dimethylformamide/ethanol/isopropanol + water

Abstract

This study investigated the solubility, solvation behavior, dissolution thermodynamics, and intermolecular interactions of 18β-glycyrrhetinic acid (GA) in binary aqueous blends of 1,4-dioxane, N,N-dimethylformamide (DMF), ethanol and isopropanol. The solubility experiments were performed using the shake-flask technique at 101.0 kPa and temperatures ranging from 278.15 to 323.15 K. The lowest and highest GA solubility was observed in water and neat organic solvent, respectively. Experiments based on XRD analysis revealed no crystal transition or solvation. Modified van't Hoff–Jouyban–Acree and Jouyban–Acree models connected the solubility with relative average deviations (RAD) not exceeding 3.63 %. The extended Hildebrand solubility parameter method was utilized here to examine the equilibrium solubility at 298.15 K, yielding a RAD of 3.95 %. According to the linear solvation energy relationship examination, the dipolarity-polarizability and solubility parameter of solutions significantly influence the solubility variation. Using the inverse Kirkwood–Buff integrals, the preferential solvation of GA by organic solvents and water was investigated quantitatively. Positive preferential solvation parameter for organic solvents in rich and moderate organic solvent blends indicated that GA was preferentially solvated by the organic solvents. GA is a Lewis acid with respect to the cosolvent molecules. Thermodynamic investigation of dissolution characteristics and enthalpy–entropy compensation revealed an endothermic process and enthalpy-driven mechanism for dissolving GA in various blends. Finally, microscopic quantitative examination of molecular surface was used to highlight the electrostatic properties of acidity/basicity of GA. The –C = O, OH, and > COOH groups are the main targets of electrophilic and nucleophilic attack. The weak interactions between GA and solvent were visually examined using an independent gradient model based on Hirshfeld partition analysis.